The mechanism by which antibodies activate platelets appears central to our understanding of the pathogenesis of a number of human diseases. These are diseases in which the interaction of anti-platelet IgG antibodies or immune complexes with platelets is associated with thrombocytopenia and thrombosis. Considerable experimental evidence supports the postulate that the platelet receptor for IgG (FcgammaR) is a key molecule mediating platelet activation by IgG antibodies. Opportunities for exploring the molecular details and consequences of antibody-platelet interaction have appeared rapidly as a result of dramatic progress in our understanding of the nature of the FcgammaR on platelets. Recently, we have seen the isolation and partial characterization of the platelet FcgammaR, the production of a monoclonal antibody against the receptor, a series of exploratory studies of FcgammaR signal transduction, a description of how anti-platelet antibodies mediate FcgammaR activation, and a realization that platelet FcgammaR clustering may underlie platelet activation by the sera of patients with heparin-induced thrombocytopenia. Much of this work has come from our efforts. We are now poised to extend these fundamental studies into a detailed analysis of the structure and function of this receptor and to dissect the participation of this receptor in antibody-mediated pathologic situations. We propose a multifaceted but well-integrated approach, moving on all frontiers that have yielded useful data, including experiments on the molecular and cell biology of the receptor and studies of platelet activation in various thrombocytopenias. The short-term aims of the project and the specific aims of this proposal are 1) to ascertain the precise structure of the platelet FcgammaR, 2) to characterize anti-FcgammaRII mab binding platelets, 3) to analyze the nature of the donor-specific variable expression of the receptor, 4) to describe the relationship of the known structural polymorphism of the receptor to various diseases, and 5) to determine how the FcgammaR is involved in anti-body mediated platelet activation. Although most of the proposed experiments focus on the fundamental mechanisms by which FcgammaR clustering activates platelets, we anticipate an expansion in our understanding of the pathogenesis of a variety of immune-mediated thrombocytopenias, such as heparin-induced thrombocytopenia and idiopathic thrombocytopenia purpura. In particular, because the thrombocytopenia of HIV infection appears associated with platelet-bound immune complexes or anti-platelet antibody, we expect to enhance our understanding of the pathogenesis of this syndrome.